This application focuses on the development of a protein mimetic concept for designing HIV-1 entry inhibitors. Protein mimetics are protein-like compounds with covalent-linked oligomers designed to mimic the bioactive quaternary structures of the gp41 trimeric coiled prehairpin and to inhibit its transition to a hairpin of six-helix-bundle commonly involved in the final step of viral membrane fusion. To stabilize their truncated oligomeric helical structure, monomeric strands are constrained by a covalent interstrand linkage at either their amino or carboxyl terminus intended to confer structural stability and to better mimic the bioactive conformation of the fuseogenic state of gp41 than their monomeric peptides. An efficient and chemoselective ligation strategy has been exploited for their preparation using unprotected peptides as monomers to arrive at chemically unambiguous protein mimetics. Preliminary results strongly support the validity of our approach. Protein mimetics exhibit significant improvements in helical structures and resistance to proteolytic degradation. More importantly, several inhibit HIV-1 at sub-nanomolar concentrations that are an order of magnitude more potent than T20, a peptide and the first approved HIV-1 entry inhibitor drug. Our short-term goals are to continue the protein-mimetic concept with added design elements to increase potency, aqueous solubility and proteolytic resistance, and to determine their mechanisms of action by biochemical and biophysical methods. Because the trimeric coiled-coil quaternary structures are found in protein-protein interactions of signaling mechanisms and type-1 envelope protein-mediated viral entry, our long-term goal is to provide a structure-driven approach to design protein mimetic inhibitors relevant to human diseases.